P518: PEDAL/EUPAL INTERNATIONAL COLLABORATION TO IMPROVE THE OUTCOME OF CHILDREN WITH RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA
Authors: V. Ceolin, S. Ishimaru, F. Bautista, B. Goemans, E. A. Kolb, L. Di Laurenzio, T. M. Cooper, M. Bakker, J. Wahlstrom, G. Sunkersett, G. Ku, C. Zwaan, D. Reinhardt, G. Nichols
Journal: HemaSphere (2022)

Background: The prognosis of children with acute myeloid leukemia (AML) has increased stepwise over the last decades, and the overall survival (OS) is currently in the 75-80% range. However, at relapse, OS is approximately 40-50%. Over the last decade, many novel drugs have been developed specifically for use in adults with AML and few have been authorized for children. Given the medical need, effective and less toxic therapies are urgently also needed for children to overcome the limitations of current intensive chemotherapy. Aims: The Leukemia & Lymphoma Society (LLS) Pediatric Acute Leukemia (PedAL) program is a strategic initiative that aims to overcome the obstacles in treating children with acute leukemia via a Transatlantic collaboration. The aim is to run a program of early and late phase clinical trials evaluating the safety and the efficacy of new agents in pediatric leukemia, eventually setting a new standard of treatment for relapsed AML. In Europe this will be implemented as a master clinical trial with sub-trials. The European Pediatric Acute Leukemia (EuPAL, including United Kingdom) consortium was set up to coordinate the European efforts for the PedAL initiative. Methods: In Europe, the current project consists of a registry protocol (EuPAL2021 Registry) and a Master protocol with sub-trials (ITCC-101). In North America patients will be enrolled in the PedAL Screening Protocol - APAL2020SC. Any patient with known or suspected relapsed or refractory AML, who is less than 22 years of age will be eligible for inclusion in the registry in Europe or in the screening protocol in North America, to provide confirmation of relapse and target expression using standardized methodologies. In Europe, the EuPAL 2021 Registry will lead to harmonization of diagnostics in country/collaborative group-specific centralized laboratories where the analysis will be carried out as part of standard of care. In North America, Australia and New Zealand APAL2020SC will utilize commercial laboratories (Hematologics, Foundation Medicine). The ITCC-101 PedAL/EuPAL Master protocol is a complex clinical trial with a stratification approach to allocate these patients to sub-trials, according to relevant biomarkers and disease related information. After confirmation of relapse, patients may be enrolled in one of the open sub-trials, provided the detailed eligibility criteria are met. Each sub-trial will effectively run as one study performed on a global scale, and data will be entered in one database. Sub-trials may not start at the same time and may be added by a substantial amendment to the master. In North America each sub-trial will be added as an amendment to the LLS Investigational New Drug. For the first wave of sub-trials, Investigational Medicinal Product prioritization was mainly achieved through international collaboration at the Pediatric Forum for AML organized by ACCELERATE Strategy Forum in April 2020. Results: The first sub-trial will be APAL2020D, an open-label Phase III randomized multicenter trial to assess if venetoclax combined with FLA+GO (fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin) will improve overall survival compared to FLA+GO, with the aim to establish the standard treatment for the 2nd relapsed AML patients (NCT05183035) and will open in Q2/Q3 2022. Summary/Conclusion: The PedAL/EuPAL international collaboration will determine, using biology-based selection markers for treatment stratification, the standards of care for AML in 1st and 2nd relapse and define the safety and efficacy parameters necessary for the efficient evaluation of novel targeted therapies.